The objective of this research project is the detailed description of the complex enzyme system that catalyzes the conversion of phenylalanine to tyrosine. The two major goals of this study are: 1) to obtain a better understanding of the regulation and the mechanism of the hydroxylation reaction catalyzed by phenylalanine hydroxylase and 2) to use this knowledge in the design of new treatments and methods for diagnosis of phenylketonuria and its variants. The discovery of a patient with phenylketonuria due to a lack of the enzyme, dihydropteridine reductase, has led to the development of a screening method for the detection of this defect using cultured skin fibroblasts. Several other cases have now been detected. We plan to continue to study the role of dihydropteridine reductase in the biosynthesis of neurotransmitters to try and elucidate the mechanisms which lead to progressive neurological deterioration in these variants.